Anti-inflammatory 3beta-hydroxy-pregn-4-ene-20-ones



United States Patent 3,186,987 ANTI-INFLAh IMATORY 3B-HYDRGXY-PREGN-4-ENE-Zil-GNES Romano Deghenghi, Westmount, Quebec, and David J.

Marshall, Montreal, Quebec, Canada, assignors to American Home ProductsCorporation, New York, N.Y., a corporation of Delaware N0 Drawing. FiledAug. 2'7, 1963, Ser. No. 304,973 15 Claims. (til. see-c3955 Thisinvention relates to biologically active steroidal alcohols, theiresters and ethers. It is also concerned with processes used in thepreparation of these compounds from known starting materials, and withthe novel intermediates used in their preparation.

More particularly it refers to biologically active ,nfipregnenolones ofthe following Formula I wherein R is hydroxyl and R" is hydrogen, ortogether R and R" are =0 (ketonic oxygen), and R is hydrogen, loweralkyl, or acyl.

Our novel compounds may also be represented by the formula identicalwith the above, but written differently, as follows:

wherein Z is selected from the group the group consisting of v ol-20-one(IXzl),

and do not possess the A -3-ketone structure of the natural corticoids.Moreover, they possess the surprising and unpredictable advantage ofexhibiting undesirable side effects to a lesser degree than otherwell-known anti-inflammatory substances.

The extent to which they cause reduction in the size and weight of thethymus gland, deposition of liver glycogen, elevation of blood sugarlevels, adrenal atrophy, excretion of sodium and potassium, or proteinbreakdown is smaller in every instance than that obtained with knownanti-inflammatory drugs. In addition the compounds of this inventionalso show a diminished degree of influence upon the blood picture.

The compounds of this invention may be prepared in the following manner.

6e fiuoro 11a-hydroxyl-pregnen-l6a,17a-isopropylidenedioXy-3,20-dione(II), the preparation of which is described in our co-pending US. patentapplication Ser. No. 310,476, filed September 20, 1963, is oxidized withchromic acid to yield the corresponding trione, Get-fluoro- 16a,17otisopropylidenedioxy 4-pregnene-3,ll,20-trione (III). The latter compoundis treated with lithium aluminum tri-t-butoxyhydride, thus selectivelyreducing only the 3-keto group, to obtaine-fiuoro-luJh-isopropylidenedioxy 4 pregnen 3 8 ol-l1,20-dione (1V),which is acetylated in the conventional manner to yield 60: fiuoro 3 ,6acetoxy 16cc,17oz-iSOpfOpf/iidfitnfidiOXY-lpregnene-1l,20-dione (V Ia).Alternatively the hydroxydiketone (IV) may also be treated witht-butylacetyl chloride in pyridine to obtain the corresponding ester,60:- fluoro 3,8-t-butylacetoxy-l6a,17a-isopropylidenedioxylpregnene-l1,2(l-dione (Vlb Alternatively, the 3-keto group of the startingmaterial (II) may also be selectively reduced with lithium aluminumtri-t-butoxyhydride to obtain the corresponding 3,8- hydroxy compound,a-fiuoro-l6a,l7oe-isopropylidenedioxy-4-pregnene-3,6,lloc-dihydroxy-20-one(VlI), the 3/3- hydroxy group of which is in turn selectively methylatedto yield the corresponding 3,8-methyl ether, 6a-fluoro- 'l6 ,17uisopropylidenedioxy-3B-methoxy-4-pregnen-1 lozol-ZO-one (VIII). Thelatter methyl ether is then oxidised in the conventional, manner toyield 6a-fiuoro-l6 x,l7a isopropylidenedioxy3fi-methoxy-4-pregnene-l1,20-dione (VIc).

The mother liquors from the crystallization of the hydroxydiketone (IV)contain the corresponding dihydroxyketone, 60: fluoro16a,17a-isopropylidenedioXy-4-pregnone-36,11,8-dihydroxy-20-one (V),which is acctylated in the conventional manner to yield thecorresponding 33- aceto iy derivative,6wfiuoro-3j8-acetoxy-l6a,l7oz-isopropylidenedioxy-4-preguen-115-ol-20-one(IXa). A1ternatively, the dihydroxy-ketone (V) is treated witht-butylacetyl chloride to obtain the corresponding 3fi-t-butylacetate,6a-fiuoro-3 fi-t-butylacetoxy-l 60:,17cz-iSOPIOPY1id6DS-dioxy-{t-pregnen-llfi-ol-ZO-one (IXb), or its 3B-hydroxy group may beselectively methylated or reacted with npropyl iodide to obtain thecorresponding methyl or propyl ethers,6e-fluoro-3fi-methoXy-16a,l7a-isopropylidenedioxyl-pregnen-l1,8-ol-20-one (lXc), or 6a-fluoro- 3,3property-16a,l7u-isopropylidenedioXy-4-pregnen-11,8-

respectively. Oxidation of the above llfi-hydroxy compounds withFormulae IXa, b, c, and d, yields the corresponding ll-keto derivativesof Formula Via, b c, or a, respectively.

The following formulae and examples will illustrate our invention.

i (VIa): R==CH GO (1X11): R= (VIb): R= otmOoH2oo (IXb): R= (vm- R=CH3(1X0 R= (VId) R 011 0 H O Ha (IXd) R EXAMPLE I I 6 ozu0r0-16a,1 7a-isopropylidenedioxy-4-pregnene- 3,11,20-27'10116 (III) A quantity of1.40 g. of 6a-fluoro-11a-hydroxy-4- pregnen-16a,l7u isopropylidenedioxy3,20 dione (see our copending application Ser. No. 310,476, filedSeptember 20, 1963), was dissolved in 40 ml. acetone and oxidized at 0C. with 2.8 m1. 8 N chromic acid during four minutes. The usual work-upgave 1.28 g. of the title product, M.P. 215 C. (dec.).

EXAMPLE II 6oc-flu0l0-16a,1 7 nt-isopropylidenedioxy-4-pregn en3B-ol-11,20-dion e (IV) The product from Example I, 100 mg., dissolvedin 2 ml. tetrahydrofuran was stirred at room temperature for 4 hourswith 182 mg. of lithium-aluminum-tri-t-butoxyhydride.

CHaCO (CHQaCCHgC O The mixture was treated with a saturated solution ofammonium sulfate and extracted with methylenedichloride. Evaporation ofthe solvent and crystallization from other gave the product, M.P. 143 C.(dec.).

EXAMPLE III 6q-flu0r0-16a,1 7 t-isopropylidenediaxy-4-pregnene- 535,11p-dihydrow-20-one (V) The mother liquors of the crystallization ofthe product described in Example 11 contained the title compound,purified by chromatography on silica-gel.

' EXAMPLE 1V 6a-fluor0-3B-zwet0xy-16uJ 7 a-isopropylidenedioxy-4-pr'e'gnene-1 1,20-dion'e (Via) The product described in Example II,583 mg., was

acetylated at room temperature for 16 hours with one ml. aceticanhydride in 5 ml. pyridine. The title comamass? pound was best purifiedby chromatography on silica gel. MP. 204 C. (dec.), +82 C. (CI-K11EXAMPLE V The compound dmcribed in Example II was treated witht-butylacetylchloride in pyridine in a manner similar to that describedin Example IV. The title compound was isolated by crystallization fromether.

EXAMPLE VI 6 ez-fl uoro-l 6 41,1 7u-isopropylidenedioxy-4-pregnene-35,11 a-dihydroxy -20-0ne (VII) In a manner analogous to that describedin Example II, but starting from 6a-fluoro-l1u-hydroxy-4-pregnen-16a,l7a-isopropylidenedioxy 3,20 dione, the title compound was obtained.

EXAMPLE VII The product from Example VI was treated with a catalyticamount of p-toluenesulfonic acid in a methanolic solution at roomtemperature for 3 hours. Partial evaporation of the solvent in vac-uoand the usual work up gave the title compound.

EXAMPLE VIII 6 lX-fl zroro-l 6 e,1 7 a-isopropylia'enedz'oxy- B-methoxy-4-pregnene-l 1 ,ZO-rzione (V) The product from Example VII was oxidizedin the usual manner with chrornic oxide in pyridine at room temperatureto give the title compound.

EXAMPLE IX 6a-flIt0r0-3 B-acetoxy-l 6 11,1 7a-isopropylidenedioxy-4-pregrren-11B-ol-20-one (I X a) In a manner similar to that describedin Example IV but starting from the product of Example III, the titlecompound was secured.

EXAMPLE X6a-fiuoro-3f3-t-butylacetoxy-I6m,17u-is0pr0pylidenedz'0xy-4-pregrzen-11fl-0l-20-0ne(IX b) Starting from product of Example III, the title compound wasobtained in a manner similar to that of Example V.

EXAMPLE XI 6:1- uor0-3fi-meth0xy-16u,17a-is0pr0pylidenedioxy-4-pregnen-11 8-0l-20-0ne (1X0) The title compound was obtained essentially in theway described in Example VII but starting from the product of ExampleIII.

Alkylation of the product described in Example III with n-propyliodidein the usual manner, afforded the title compound.

EXAMPLE XIII 6 a-flr10r0-3 S-propoxy-l 6 0a,] 7a-is0pr0pylidenedioxy4-pregnene-1 1 ,2 O-dione VI d The product frnm Example XII was oxidizedwith chromic anhydride in pyridine in the conventional manner at roomtemperature and the title compound was thereby secured.

6 We claim: 1. Pregnenolone derivatives of the formula =0 I a Z/\ O\C/CHI 0 \CH3 I RO- in which Z is selected from the group consisting of and0:0

and R is selected from the group consisting of hydrogen, lower alkyl,and lower alkanoyl. 2. Pregnenol-one derivatives of the formula E ---oCH3 0O 0 x \O/ 0 om WQIJ in which R is selected from the groupconsisting of hydrogen, lower alkyl, and lower alkanoyl.

3. Pregnenolone derivatives of the formula

1. PREGNENOLONE DERIVATIVES OF THE FORMULA